WASHINGTON -- Philip Noguchi, acting director of the Divisionof Cellular and Gene Therapies at FDA, addressed the agency'sconcern about safety of vectors in viral vaccines here onMonday at a session of the BioEast conference on productionand downstream processing of retroviral vectors.
The first lot of Salk polio vaccine, Noguchi recalled, actuallycaused some cases of the disease. The problem, unknown at thetime, was that without enough formaldehyde in the solution,the reaction that disabled the polio vaccine was reversible.
Last Oct. 26 an advisory committee to the Center for BiologicsEvaluation and Research (CBER) judged the risk from vectors tobe quite small. Nonetheless, FDA is pursuing the matterrelentlessly.
One danger was demonstrated in recent experiments by ArthurNienhius of the National Heart Lung and Blood Institute. Certainreplication-competent retroviruses can cause malignancies,such as lymphomas in experimental monkeys, under veryadverse conditions, such as complete bone marrowimmunosuppression or extended retroviremia.
This puts the five children treated for adenosine deaminasedeficiency at very low risk, Noguchi told BioWorld, "(but) wedon't have a good idea of the mechanism or what factors arepredisposing."
As discussed at the Oct. 26 meeting, there is an easy, well-accepted test that can detect replication competentretroviruses, and if the test is negative, the probability of theirpresence is about nil.
As for adenoviruses, most of the virus particles in anypreparation for gene therapy are capsids, which are empty orcontain some non-viral material. The concentration of vectorsto these useless capsids must be high enough for efficacy butlow enough that no adverse reactions are caused. Thetherapeutic window between the two boundaries is narrow,Noguchi said.
Bottom line: The dangers of adenoviruses are very small sincemultiple safeguards are available, said Noguchi, but FDA is stillsupporting proactive research to anticipate risks that could haltprogress in the event of a potentially dangerous occurance.
Genzyme Corp. and Michael Welsh of the University of Iowaand Howard Hughes Medical Research Foundation found no illeffects when a Genzyme adenovirus vector was used to insertthe cystic fibrosis transmembrane regulatory (CFTR) gene intothree patients' nasal epitheliums.
In Genzyme's next clinical trial, which has been approved bythe Recombinant DNA Advisory Committee of the NationalInstitutes of Health, the researchers will use a version of thevector that has been modified by removal of a portion of the E4region.
That confers two advantages. First, E4 functions are requiredfor regulation of late viral gene expression and viral DNAreplication, so the modified vector has a reduced probability ofreplication competence. Second, the deletion provides morespace for insertion of theraputic genes, said SamuelWadsworth, director of molecular biology at Genzyme. Hediscussed the research at Monday's BioEast meeting. However,the virus uses a promotor that is superior to that of itspredecessor. This phosphoglycerate kinase promotor isexpressed in virtually all cells and should improve expressionof the CFTR gene, said Wadsworth.
As for the problem of the narrow theraputic window,Wadsworth said Genzyme would emphasize safety and aim forthe lowest particle to plaque forming unit (empty andrandomly occupied capsids) possible.
Genzyme's clinical trial will test the safety of repeated doses ofthe gene since that will be required in actual gene therapy.Target tissues will be the nasal epithelium and the maxillarysinus for each of two sets of five to 10 patients.
The four-day conference is being sponsored by theInternational Federation for the Advancement of GeneticEngineering and Biotechnology and Genetic Engineering News.
-- David Holzman Washington Editor
(c) 1997 American Health Consultants. All rights reserved.